ARB: Phase II window of opportunity study of short-term preoperative treatment with enzalutamide in ER-positive and triple-negative breast cancer

The androgen receptor (AR) is expressed in 60-80% of breast cancers (BC) across all molecular phenotypes, with a higher incidence in oestrogen receptor positive (ER+) BC compared to ER negative tumours. In ER+ disease, AR-expression has been linked to endocrine resistance which might be reversed with combined treatment targeting ER and AR. In triple negative BCs (TNBC), preclinical and clinical investigations have described a subset of patients that express the AR and are sensitive to androgen blockade, providing a novel therapeutic target. Enzalutamide, a potent 2nd generation anti-androgen, has demonstrated substantial preclinical and clinical anti-tumour activity in AR+ breast cancer. Short-term preoperative window of opportunity studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. The ARB study aims to assess the anti-tumour effects of enzalutamide in early ER+ breast cancer and TNBC, to identify the optimal target population for further studies and to directly explore the biologic effects of enzalutamide on BC and stromal cells. Methods: ARB is an international, investigator sponsored WOO phase II study in women with newly diagnosed primary ER+ BC or AR+ TNBC of ≥ 1cm. The study has two cohorts. In the ER+ cohort, postmenopausal patients will be randomised 2:1 to receive either enzalutamide (160mg OD) plus exemestane (50mg OD) or exemestane (25mg OD). In the TNBC cohort, AR+ will receive single agent treatment with enzalutamide (160mg OD). Study treatment is planned for 15–29 days, followed by surgery or neo-adjuvant therapy. Tissue and blood samples are collected before treatment and on the last day of study treatment. The primary endpoint is inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3), circulating hormone levels and safety. ARB aims to recruit ≈235 patients from ≈40 sites in the UK, Germany, Spain and USA. The study is open to recruitment.

The New Architecture of EU Equality Law after CHEZ: Did the Court of Justice reconceptualise direct and indirect discrimination?

The Court of Justice’s decision of the 16 July 2015, in Case C-83/14 CHEZ Razpredelenie Bulgaria AD v Komisia za zashtita ot diskriminatsia, is a critically important case for two main reasons. First, it represents a further step along the path of addressing ethnic discrimination against Roma communities in Europe, particularly in Bulgaria, where the case arises. Second, it provides interpretations (sometimes controversial interpretations) of core concepts in the EU antidiscrimination Directives that will be drawn on in the application of equality law well beyond Bulgaria, and well beyond the pressing problem of ethnic discrimination against Roma. This article focuses particularly on the second issue, the potentially broader implications of the case. In particular, it will ask whether the Court of Justice’s approach in CHEZ is subtly redrawing the boundaries of EU equality law in general, in particular by expanding the concept of direct discrimination, or whether the result and the approach adopted is sui generis, one depending on the particular context of the case and the fact that it involves allegations of discrimination against Roma, and therefore of limited general application.

From Crisis to Opportunity: Turnaround Strategies of Large Irish Construction Contractors During the Period 2007-2015.

The sudden change in environmental munificence level in the construction sector
during the period 2007 – 2015 provides a natural experiment to investigate strategic
and operating actions of firms, particularly during an environmental jolt. Statistics on
business failures corroborate that neither academics nor practitioners have succeeded
in guiding strategic action during periods of environmental jolt. Despite the recent
increase of turnaround research in the general management domain, its use in the
construction management realm remains underexplored. To address this research
gap, five exploratory case studies of an ongoing PhD study were used to examine the
turnaround strategies of construction contractors during a period of economic
contraction and growth. The findings show that, although retrenchment is often
considered to be a short-term strategy, this is clearly not the case; with the majority of
contractors maintaining the strategy for 6-7 years. During the same period,
internationalization became critical, with the turnaround process shifting towards
strategic reorientation that altered the firms' market domain. The case studies further
suggest that strategic and operational actions resonate quite well with contemporary
practice-based approaches to strategy making. The findings provide valuable
assistance for construction contractors in dealing with organisational decline and in
developing a successful turnaround response.